Erythrocytosis and polycythaemia — Frequently asked questions (FAQ)
1) What does this algorithm cover?
The algorithm guides the diagnostic approach to patients with elevated haemoglobin/haematocrit, from confirmation of persistence and exclusion of relative polycythaemia — haemoconcentration, to differentiation between primary erythrocytosis — for example polycythaemia vera — and secondary erythrocytosis — chronic/intermittent hypoxia, inappropriate EPO production, drugs. It integrates the main decision tests, including serum erythropoietin and JAK2, and defines when to refer to Haematology.
2) What is the difference between “polycythaemia” and “erythrocytosis”?
Erythrocytosis describes increased red cell mass — or, in practice, persistent Hb/Ht above the expected range. The term polycythaemia is often used generically, but should preferably be reserved for specific entities such as polycythaemia vera — a myeloproliferative neoplasm. The algorithm uses the clinical logic of “erythrocytosis” until there is evidence of a primary cause — for example positive JAK2 with compatible criteria.
3) Why is it essential to confirm persistence before investigating?
A single full blood count may reflect biological variation, transient haemoconcentration or intercurrent factors — fever, diarrhoea, low fluid intake. Confirmation with ≥2 full blood counts at different time points reduces false positives and avoids unnecessary investigation. If values are very high, symptoms of hyperviscosity or thrombotic events are present, assessment should be accelerated without waiting for prolonged intervals.
4) How do I exclude relative polycythaemia — haemoconcentration — in practice?
Dehydration and diuretic use should be assessed through targeted history — vomiting/diarrhoea, fever, intense sweating, rapid weight loss, low fluid intake —, signs of hypovolaemia on examination — dry mucous membranes, orthostatic hypotension, tachycardia — and the typical laboratory pattern — ↑ Hb/Ht with normal white blood cells and platelets, sometimes with elevated albumin/proteins. If suspected, the cause should be corrected and the full blood count repeated in 2–4 weeks.
5) What is the role of erythropoietin — EPO — in decision-making?
Serum erythropoietin is the main “divider” in the algorithm. Subnormal EPO suggests primary erythrocytosis — often polycythaemia vera — and justifies molecular testing — JAK2. Normal/elevated EPO points towards secondary erythrocytosis, and evaluation of hypoxia and EPO-dependent causes — renal/hepatic tumours, drugs, exogenous EPO — should be prioritised.
6) When should polycythaemia vera be suspected?
Polycythaemia vera should be suspected in the presence of persistently elevated Hb/Ht, especially when signs/symptoms coexist, such as aquagenic pruritus, plethora, headaches, thrombotic events or splenomegaly. Supporting laboratory findings include leukocytosis, thrombocytosis, low ferritin — associated iron deficiency — and often low EPO. The algorithm guides confirmation with JAK2 and assessment in Haematology.
7) Which tests should I request when EPO is low?
In the presence of subnormal EPO, the next step is to screen for JAK2 V617F. If negative, JAK2 exon 12 should be tested. In cases with strong suspicion and negative tests, the decision regarding bone marrow biopsy/assessment and differential diagnosis of other myeloproliferative neoplasms should be conducted in a Haematology consultation.
8) How should hypoxia be assessed in a structured way?
Assessment should include resting SpO₂ — values <92–94% suggest clinically relevant hypoxia — but normal SpO₂ does not exclude intermittent hypoxia. A targeted history should assess COPD, interstitial lung disease, congenital heart disease, altitude and smoking. If obstructive sleep apnoea syndrome is suspected — snoring, witnessed apnoeas, daytime sleepiness — overnight oximetry and/or polysomnography are recommended. In heavy smokers, carboxyhaemoglobin should be considered; if lung disease is suspected, arterial blood gas analysis and pulmonary function tests may be useful.
9) What are the most relevant EPO-dependent causes?
When EPO is elevated and there is no evident hypoxia, causes of inappropriate EPO production should be considered, including renal and hepatic tumours — for example renal cell carcinoma, hepatocellular carcinoma — and, more rarely, other neoplasms. Exogenous EPO, testosterone/anabolic steroids and other exposures associated with erythrocytosis should also be assessed. The algorithm helps decide when to proceed to imaging and referral.
10) Which drugs can cause erythrocytosis?
The classic drugs are testosterone and other androgens/anabolic steroids, as well as exogenous erythropoietin. In some patients, an increase in Hb/Ht may be observed with therapies such as SGLT2 inhibitors — multifactorial mechanism. Whenever the chronology is suggestive, suspension/adjustment should be considered according to risk-benefit and clinical context.
11) When should I refer to Haematology?
Referral is recommended when there is suspicion of polycythaemia vera — particularly with low EPO, positive JAK2 or suggestive clinical signs —, when erythrocytosis persists without an identifiable secondary cause, or when idiopathic/hereditary erythrocytosis is suspected — young age, family history, normal/high EPO, negative secondary work-up. It should also be considered in situations with thrombosis, symptoms of hyperviscosity or need for a specific therapeutic decision.
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